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US 12,753,179 B2Granted
FGFR inhibitor compound and use thereof
AssigneeShenzhen Kangsu Pharmaceutical Technology Co., Ltd.
InventorsLiang Lu, Saisai Zhao, Hai Huang, Longzheng Zhang, Jixuan Zhang, Jiaxin Chen, Shancun Ling
Life of this patent
Estimating the term…
Abstract
The present disclosure relates to FGFR inhibitor compounds and its use. Specifically, the present disclosure discloses a compound represented by formula (I), isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. The present disclosure also relates to use of the above compound in medicine.
Claims18
A compound of Formula (I),
- or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof,
- wherein
- R1 and R2 are each independently selected from H, halogen, —CN, OH, —NO2, —NR7R8, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 alicyclic group, and 4-6 membered heteroalicyclic group;
- and
- R3 is selected from H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 alicyclic group, and 4-6 membered heteroalicyclic group;
- and
- 1, 2 or 3 R6(s) are present in formula (I), and each R6 is independently selected from H, halogen, —CN, —OH, —NO2, —NR7R8, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 alicyclic group, and 4-6 membered heteroalicyclic group;
- and
- X is O, S or (NR4) in which R4 is selected from H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 alicyclic group, and 4-6 membered heteroalicyclic group;
- and
- R7 and R8, at each occurrence, are each independently selected from H, C1-6 alkyl, C1-4 haloalkyl, and C1-4 alkoxy, or R7 and R8 and the atom(s) attached thereto together form a 3-6-membered ring;
- and
- n=1, 2 or 3;
- and
- L is (C=O), (O═S=O), ((C═O)—CH2) or a bond;
- and
- R5 is selected from H, halogen, —OH, —NO2, —CN, —SF5, —SH, —S—C1-4 alkyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-7 alicyclic group, 3-10 membered heteroalicyclic group, C6-12 bicyclic alicyclic group, 6-12 membered bicyclic heteroalicyclic group, C8-15 tricyclic alicyclic group, 8-15 membered tricyclic heteroalicyclic group, C5-8 aryl, 5-10 membered heteroaryl, C7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, —C1-4 alkyl-(C3-7 alicyclic group), —C1-4 alkyl-(3-10 membered heteroalicyclic group), —C1-4 alkyl-(C6-12 bicyclic alicyclic group), —C1-4 alkyl-(6-12 membered bicyclic heteroalicyclic group), —C1-4 alkyl-(C8-15 tricyclic alicyclic group), —C1-4 alkyl-(8-15 membered tricyclic heteroalicyclic group), —C1-4 alkyl-(C5-8 aryl), —C1-4 alkyl-(5-10 membered heteroaryl), —N(R10)(R11), —N(R10)(C(═O)R11), —N(R10)(C(═O)—OR11), —N(R12)(C(═O)—N(R10)(R11)), —C(═O)—N(R10)(R11), —C(═O)—R12, —C(═O)—OR12, —OC(═O)R12, —N(R10)(S(═O)2R11), —S(═O)2—N(R10)(R11), —SR12, and —OR12, wherein the —S—C1-4 alkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-7 alicyclic group, 3-10 membered heteroalicyclic group, C6-12 bicyclic alicyclic group, 6-12 membered bicyclic heteroalicyclic group, C8-15 tricyclic alicyclic group, 8-15 membered tricyclic heteroalicyclic group, C5-8 aryl, 5-7 membered heteroaryl, C7-11 bicycloaryl, 7-11 membered bicyclic heteroaryl, —C1-4 alkyl-(C3-7 alicyclic group), —C1-4 alkyl-(3-10 membered heteroalicyclic group), —C1-4 alkyl-(C6-12 bicyclic alicyclic group), —C1-4 alkyl-(6-12 membered bicyclic heteroalicyclic group), —C1-4 alkyl-(C8-15 tricyclic alicyclic group), —C1-4 alkyl-(8-15 membered tricyclic heteroalicyclic group), —C1-4 alkyl-(C5-8 aryl), and —C1-4 alkyl-(5-10 membered heteroaryl) are each optionally substituted with 0, 1, 2, 3 or 4 R5a;
- and R5a is independently selected from halogen, —OH, —NO2, —CN, —SF5, —SH, —S—C1-4 alkyl, oxo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-7 alicyclic group, 3-10 membered heteroalicyclic group, C5-8 aryl, 5-7 membered heteroaryl, —N(R13)(R14), —N(R13)(C(═O)R14), —N(R13)(C(═O)—OR14), —N(R15)(C(═O)—N(R13)(R14)) —C(═O)—N(R13)(R14), —C(═O)—R15, —C(═O)—OR15, —OC(═O)R15, —N(R13)(S(═O)2R14), —S(═O)2—N(R13)(R14), —SR15, and —OR15;
- and
- R10, R1, R12, R13, R14 and R15, at each occurrence, are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 alicyclic group, 3-10 membered heteroalicyclic group, C5-8 aryl, 5-7 membered heteroaryl, C7-11 bicycloaryl, 7-11 membered bicyclic heteroaryl, —C1-4 alkyl-(C3-7 alicyclic group), —C1-4 alkyl-(3-10 membered heteroalicyclic group), —C1-4 alkyl-(C6-12 bicyclic alicyclic group), —C1-4 alkyl-(6-12 membered bicyclic heteroalicyclic group), —C1-4 alkyl-(C8-15 tricyclic alicyclic group), —C1-4 alkyl-(8-15 membered tricyclic heteroalicyclic group), —C1-4 alkyl-(C5-8 aryl), and —C1-4 alkyl-(5-10 membered heteroaryl), wherein each substituent listed in the group is optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from a group consisting of:
- halogen, —OH, —NH2, —NH(CH3), —N(CH3)2, —CN, —NO2, —SF5, —SH, —S—C1-4 alkyl, oxo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 alicyclic group, 3-10 membered heteroalicyclic group, C5-8 aryl, 5-7 membered heteroaryl, C7-11 bicycloaryl, 7-11 membered bicyclic heteroaryl, C1-4 hydroxyalkyl, —S—C1-4 alkyl, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy and C1-4 haloalkoxy;
- or R10, R11, and the atom(s) attached thereto together form a 3-14-membered ring;
- or R13, R14, and the atom(s) attached thereto together form a 3-14-membered ring.
20 more elements
A compound selected from:
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-methylpiperazin-1-yl)ketone;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-((1-methylpiperidin-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(1-methylpiperidin-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-5-(1-methylpiperidin-4-yl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine;
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)(4-methylpiperazin-1-yl)ketone;
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methylpiperidin-4-yl)ketone;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(pyridin-3-ylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(morpholinyl)ketone;
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((R)-pyrrolidin-3-yl)ketone;
- (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((S)-3-hydroxypyrrolidin-1-yl)ketone;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 4-(2-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethyl)morpholine;
- 1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-morpholinoethan-1-one;
- 1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(dimethylamino)ethan-1-one;
- 2-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethan-1-ol;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- Methyl 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxylate;
- Methyl (R)-2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxylate;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 3-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)cyclobutan-1-ol;
- 4-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)cyclohexan-1-ol;
- Ethyl 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazole-5(1H)-carboxylate;
- 2-Cyanoethyl 2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate;
- Cyclopropyl (2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;
- (2-(5-(1-(3, 5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxycyclobutyl)ketone;
- 3-(2-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazol-5(1H)-yl)-3-oxopropane-carbonitrile;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(ethylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 3-(5-(cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole;
- 5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(isopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(3-hydroxypyrrolidin-1-yl)ethan-1-one;
- 1-(2-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo [3,4-d]imidazol-5(1H)-yl)-2-oxoethyl)pyrrolidine-3-carbonitrile;
- (R)-2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide;
- (R)-2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide;
- (R)-2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide;
- 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(1-methylpyrrolidin-3-yl)-1,4,5,6-tetrahydropyrrolo[3, 4-d]imidazol-2-yl)-1H-indazole;
- 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(1-(1-methylpiperidin-4-yl)ethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(1-methylpiperidin-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(1-(methylsulfonyl)pyrrolidin-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole;
- (R)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(pyrrolidin-1-yl)ethan-1-one;
- 1-(2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethan-1-one;
- 1-(2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-((S)-3-hydroxypyrrolidin-1-yl)ethan-1-one;
- (R)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(dimethylamino)ethan-1-one;
- 3-(5-(L-prolyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole;
- 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-(methyl-L-prolyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H indazole;
- (2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((S)-piperidin-2-yl)ketone;
- (2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)((S)-1-methylpiperidin-2-yl)ketone;
- 1-(2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(3-fluoropyrrolidin-1-yl)ethan-1-one;
- 1-(2-(2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-oxyethyl)pyrrolidine-3-carbonitrile;
- (R)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(piperidin-1-yl)ethan-1-one;
- (R)-2-(azetidin-1-yl)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ethan-1-one;
- (R)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(3-hydroxyazetidin-1-yl)ethan-1-one;
- (R)-1-(2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-2-(3-fluoroazetidin-1-yl)ethan-1-one;
- 2-(dimethylamino)ethyl (R)-2-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate;
- 1-methylpyrrolidin-3-yl 2-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate;
- or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof.
55 more elements
Dependencies are inferred from the claim text.